Erythropoietin (Epo) is the principal hematopoietic growth factor that promotes the viability, differentiation and proliferation of mammalian erythroid progenitor cells (S. Krantz, Blood 77, 419-34 (1991)). The biologic effects of Epo are mediated via its interaction with its specific transmembrane receptor, EpoR (H. Youssoufian, Blood 81, 2223-36 (1993)). The EpoR lacks intrinsic tyrosine kinase activity and upon ligand binding activates a receptor-associated tyrosine kinase Jak2 which is critical for anti-apoptosis and mitogenic signaling via the EpoR (O. Miura et al., Blood 84, 1501-7 (1994); B. Witthuhn et al., Cell 74, 227-36 (1993); J. Ihle, Nature 337, 591-4 (1995); H. Zhuang et al., J. Biol Chem. 270, 14500-4 (1995)). Activated Jak2 then phosphorylates a number of cytoplasmic proteins as well as the EpoR itself. Expression of Epo receptors has been reported on several non-hematopoietic cell types including vascular endothelial cells, placental tissue, neuronal cells, kidney and cardiomyocytes (A. Anagnostou et al., Proc. Natl. Acad. Sci. USA 91, 3974-8 (1994); S. Masuda et al., J. Biol. Chem. 268, 112-8-16 (1993); S. Sawyer et al., Blood 74, 103-9 (1989); M. Wald et al., J. Ce. Physiol. 167, 461-8 (1996)).
Recombinant human Epo (r-HuEpo) has been widely used in many different types of cancers for the treatment or prevention of chemo-radiotherapy induced anemia (A. Moliterno and J. Spivak, Hematol. Oncol. Clin. North Am. 10, 345-63 (1996)). For instance, in patients with breast cancer, r-HuEpo has been investigated in clinical trials for its potential beneficial effects in the prevention or treatment of chemotherapy or radiation therapy-related anemia (L. Del Mastro et al., J. Clin. Oncol. 15, 2715-21 (1997); H. Ludwig et al., Ann. Oncol. 4, 161-7 (1993); P. Sweeney et al., Br. J. Cancer 77, 1996-2002 (1998); S. Vijayakumar et al., Int. J. Radiat. Oncol. Biol. Phys 26, 721-9 (1993)), for mobilization of peripheral blood progenitor cells (C. Waller et al., Bone Marrow Transplant 24, 19-24 (1999)), to increase the rate of hematopoietic recovery following high dose chemotherapy (P. Benedetti Panici et al., Br. J. Cancer 75, 1205-12 (1997); S. Filip et al., Neoplasma 46, 166-72 (1999)) as well as use in ex vivo expansion strategies of stem cells (C. Bachier et al., Exp Hematol. 27, 615-23 (1999); L. Pierelli et al., Exp. Hematol. 27, 416-24 (1999); P. Stiff et al., Blood 95, 2169-74 (2000); W. Vogel et al., Blood 86, 1362-7 (1996)). Similarly, r-HuEpo has been investigated in several clinical trials of squamous cell cancers of head-neck (F. Dunphy et al., Cancer 86, 1362-7 (1999); M. Henke et al., radiother Oncol 50, 185-90 (1999); G. Mantovani et al., Oncol. Rep. 6, 421-6 (1999)) and uterine cervix (K. Dusenbery et al., Int. J. Radial. Oncol. Biol. Phys. 29, 1079-84 (1994)).
In view of the foregoing, it would be extremely desirable to understand the association of Epo with tumor growth and how EpoR may be involved in cancer pathophysiology and progression.